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Ideas and Opinions |

Let's Not SPRINT to Judgment About New Blood Pressure GoalsLet's Not SPRINT to Judgment About New BP Goals

Eduardo Ortiz, MD, MPH; and Paul A. James, MD
[+] Article, Author, and Disclosure Information

This article was published at www.annals.org on 23 February 2016.


From Washington, DC, and University of Iowa, Iowa City, Iowa.

Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-3123.

Requests for Single Reprints: Paul A. James, MD, University of Iowa, 200 Hawkins Drive, 01286-D PFP, Iowa City, IA 52242; e-mail, paul-james@uiowa.edu.

Current Author Addresses: Dr. James: University of Iowa, 200 Hawkins Drive, 01286-D PFP, Iowa City, IA 52242.

Dr. Ortiz: 2318 Mill Road, Suite 800, Alexandria, VA 22314; e-mail, comment-ortiz@outlook.com.

Author Contributions: Conception and design: E. Ortiz, P.A. James.

Analysis and interpretation of the data: E. Ortiz, P.A. James.

Drafting of the article: E. Ortiz, P.A. James.

Critical revision for important intellectual content: E. Ortiz, P.A. James.

Final approval of the article: E. Ortiz, P.A. James.

Statistical expertise: E. Ortiz, P.A. James.

Administrative, technical, or logistic support: E. Ortiz, P.A. James.

Collection and assembly of data: E. Ortiz, P.A. James.


Ann Intern Med. 2016;164(10):692-693. doi:10.7326/M15-3123
© 2016 American College of Physicians
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The randomized trial SPRINT (Systolic Blood Pressure Intervention Trial) compared aggressive treatment to a target systolic blood pressure less than 120 mm Hg versus less than 140 mm Hg in patients with increased cardiovascular risk and found a 25% relative risk reduction in cardiovascular events. This commentary discusses the trial and its implications.

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Reply to Ortiz and James from the SPRINT Research Group:
Posted on March 11, 2016
Cora E. Lewis, MD, MSPH, FAHA, FACP; Karen C. Johnson, MD, MPH, FAHA; Mahboob Rahman, MD; Kaycee M. Sink, MD, MAS; Walter T. Ambrosius, PhD; for the SPRINT Research Group
Division of Preventive Medicine, University of Alabama at Birmingham School of Medicine (CEL)
Conflict of Interest: All authors are investigators and receive support from NIH for the SPRINT trial
Ortiz and James (1) state that the absolute risk reduction for the SPRINT primary outcome with intensive compared to standard systolic blood pressure (SBP) treatment goal (16 events/ 1000 treated) is outweighed by the absolute risk of harm (22 events/1000) over 3.2 years. More accurately, these are: benefit 18 events/1000, harm 23 events/1000, over 3.26 years median follow-up.

Their comparison overemphasizes harms by focusing on the small fraction of serious adverse events (SAEs) deemed potentially related to intervention, rather than the total SAEs, which were not different between groups. They put the risk of decompensated heart failure, cardiovascular death, and other primary outcomes, benefited by intensive treatment, on equal footing with risk of syncope, electrolyte abnormality, hypotension, and acute kidney injury (2), which occurred less commonly than knee arthroplasty in SPRINT.

They minimize benefits by ignoring the 27% total mortality reduction (2), also important to patients and more consequential than syncope and the like. In clinical practice, these AEs would likely be handled by treatment adjustment, mostly without long-term sequelae. On the other hand, benefits would reasonably be expected to further accumulate over time in patients tolerant to intensive therapy.

Some Intervention-related SAEs may have been over-reported in the intensive group. These conditions were prospectively identified; participants were not masked to treatment assignment and were warned of these conditions in consent forms. The intensive group had approximately 30% more study visits and thus greater opportunity to report AEs, leading to possible ascertainment bias, which did not exist for the study outcomes equally ascertained in both groups.

The SPRINT comparison group, SBP goal <140 mm Hg, was recommended in guidelines current at trial inception (3). Yet, Ortiz and James state both SPRINT groups were over treated compared to the <150 mm Hg goal they advocated in 2014 (4), a controversial recommendation (5) that came years after SPRINT started.

Finally, Ortiz and James argue against pursuing the intensive SBP goal in a hypothetical 79 year old patient already on antihypertensive medication. However, all age groups benefited equally in SPRINT and this patient has higher absolute cardiovascular risk and thus greater potential benefit than a hypothetical 55 year old patient they recommend treating more intensively.

SPRINT will continue publications, including data on in-depth safety and benefits in participants aged ≥ 75 years as well as quality of life and kidney outcomes, to inform future guidelines.

REFERENCES
1. Ortiz E, James PA. Let’s not SPRINT to judgement about blood pressure goals. Ann Intern Med; Published online 23 February 2016 doi:10.7326/M15-3123
2. Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, et al; SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015; Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, et al; SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373:2103-16. [PMID 26551272] doi: 10.1056/NEJMoa1511939
3. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42:1206-1252.
4. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507-20. [PMID: 24352797] doi:10.1001/jama.2013.284427
5. Chazal RA, Creager MA. New Quality Measure Core Sets Provide Continuity for Measuring Quality Improvement : Concerns Raised About Conflicting BP Measures. Hypertension 2016;67: 000–000. Published online before print February 16 2016, doi:10.1161/HYP.0000000000000043
Author's Response
Posted on August 12, 2016
Eduardo Ortiz, MD, Paul A James, MD
University of Iowa
Conflict of Interest: None Declared
We thank the SPRINT investigators and appreciate their perspective. They suggest we understate the benefits and exaggerate the harms from SPRINT (1). While we agree that relative risk reduction (RRR) is an important measure of clinical effect, it is incomplete and should be interpreted in the context of Absolute Risk Reduction (ARR) (2). We stand by our assertion that a more balanced interpretation of clinical trials should use established evidence-based medicine (EBM) principles to assess clinical effectiveness (3).
SPRINT showed that 1.6% (ARR) of participants benefited from more aggressive treatment to a lower blood pressure (BP) goal while 98% of participants treated aggressively had no benefit at 3.2 years. Those 98% were subjected to more treatment, more visits, more costs, more disease labeling, and in some cases, more harm, without any benefit. We believe the investigators conflate treatment for a disease (e.g., hypertension) with that of treatment for a risk factor (e.g., BP < 140 mmHg) in both their design and interpretation of SPRINT. While the RRR may be similar for both groups, the differences in ARR guide us to different conclusions about treatment effectiveness.
We agree with the investigators that the outcomes studied are generally more serious to individual patients than the harms suffered from the treatment but do not agree that this is the appropriate comparison. Harms suffered may be justifiable to an individual if the offending treatment is likely to benefit that individual over time, which is not the case for 98% of SPRINT participants. The investigators discount the intensity of their intervention on a largely asymptomatic population, and more medications, more doctor visits, and higher out-of-pocket costs are not viewed favorably by most patients.
The investigators assume that when harms occur, they will be detected and corrected with minimal or no sequelae. This seems logical in a clinical trial where patients are seen regularly and monitored closely, but that is not what occurs in practice where follow-up is less reliable. In tightly controlled clinical trials, benefits are often exaggerated and harms minimized (4) because they are conducted under ideal conditions with protocols, expert clinicians, select patients, and close follow-up/monitoring.
In summary, we believe SPRINT is an important study whose results should be applied judiciously in select patients incorporating EBM principles, patient preferences and individualized informed shared decision-making to ensure that patients treated more aggressively truly have a high likelihood of benefit from the intervention without being harmed.

Eduardo Ortiz, MD, MPH
Paul A. James, MD


References
1. The SPRINT Investigators Research Group. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. 2015;373(22):2103-16.
2. Carrasco-Labra A MV, Ioannidis JA, Jaeschke R, Devereaux P, Walsh M, Schünemann HJ, Bhandari M, Guyatt G. Misleading Presentations of Clinical Trial Results. In: Guyatt G RD, Meade MO, Cook DJ., editor. Users' Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice, 3rd ed. New York, NY: McGraw-Hill; 2015. http://jamaevidence.mhmedical.com/content.aspx?bookid=847&Sectionid=69031482.; 2015.
3. Ortiz E, James PA. Let's Not SPRINT to Judgment About New Blood Pressure Goals. Ann Intern Med. 2016;164(10):692-3.
4. Olsen LA, McGinnis JM. Roundtable on Value & Science-Driven Health Care. Redesigning the Clinical Effectiveness Research Paradigm: Innovation and Practice-Based Approaches: Workshop Summary. Institute of Medicine. Washington, DC: The National Academies Press; 2010.



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